The major objective of the KEEPS (Kronos Early Estrogen Prevention Study) Cognitive and Affective Study is to evaluate the potential differential efficacy of oral conjugated equine estrogen (CEE or Premarin) and transdermal 17 -estradiol (tE2) on mood and cognitive function of healthy perimenopausal women over an extended therapy of 4 years. Recent findings from the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS) have raised serious concerns about the long-term safety of both the unopposed and opposed CEE. Additionally, these studies have raised several issues related to HT that need to be systematically evaluated in well-designed clinical studies. These issues include the following: 1) which is the best period in a woman's reproductive history to initiate hormone therapy (perimenopausal versus postmenopausal), 2) what is the preferred form of estrogen therapy (CEE versus estradiol), 3) which is the most effective route of administration of estrogen (oral vs. transdermal), 4) which is the best progestin for opposed hormone therapy (natural progesterone vs. medroxyprogesterone), 5) what are the most sensitive psychometric measures to characterize potential effects of estrogen on cognition and mood, and 6) which hormone therapy regimen is physiologically most relevant and mimics the menstrual cycle hormonal milieu (continuous vs. cyclic). The KEEPS Cognitive and Affective (C/A) Study is the first multisite, randomized, placebo-controlled, double-blind, parallel-group design clinical study that will address major HT-related issues raised by WHI and WHIMS. Specifically, the C/A Study will involve perimenopausal women and evaluate the differential efficacy of CEE and tE2 on comprehensive measures of cognition and mood in perimenopausal women over an extended therapy of four years. The present study will employ cyclic administration of micronized progesterone to counteract proliferative effects of HT on the endometrium, and accomplish the following objectives: 1) to characterize the potential differential efficacy and adverse effect profile of extended therapy with CEE and tE2 on cognitive function of perimenopausal women, 2) to identify the effects of micronized progesterone on the proposed battery of cognitive and affective tests in perimenopausal women, 3) to establish the relationship between estrogen-induced changes in markers of atherosclerosis, heart disease, and measures of mood and cognition, 4) to characterize the relationship between estrogen-related changes in proposed markers of inflammation, blood hypercoagulability, and tests of cognition and mood, and 5) to determine if ApoE genotype will influence cognitive responsitivity to HT.